Recently, cerebral microvessel disease has been identified as an important component of Alzheimer's disease. The mechanism of interaction between the diseases is still unclear in part because animal models of microvascular disease are lacking. The proposed work studies the interrelationship between microvascular damage and the accumulation of Ap, the dominant characteristic of Alzheimer's disease. This work builds on the clinical observation that the severity of dementia in Alzheimer's disease is often related to the presence of vascular disease. We use novel optical tools to induce microvascular lesions in transgenic mouse models of Alzheimer's disease and then image the progression of the resulting pathology. Our lesioning technique, femtosecond laser ablation, can disrupt individual microvessels as deep as 500 pm beneath the cortical surface. The study includes multiple types of microvascular lesions, including hemorrhages, ischemic occlusions and transient leakages, all of which potentially contribute to disease progression. Two-photon excited fluorescence microscopy is used to image amyloid plaque development and to measure blood flow and leakage in the microvasculature. This allows time-lapsed study of both the microvascular lesion and amyloid plaque. Post-mortem labeling with A(3 antibodies will be used to further elucidate the impact of the microvascular lesion on Ap accumulation. In Aim 1, we test whether microvascular clots and hemorrhages trigger rapid amyloid plaque formation at different locations in the vascular tree. In Aim 2, we ask if vascular lesions earlier in life can induce a predisposition to plaques later. In the final aim, we determine where plaques that are seeded by vascular lesions are relative to different cell types and determine whether inflammation or reactive oxygen species are factors through colocalization studies. In addition, we use histological and immunohistological assays to identify the affected cells and map the Ap accumulation. Our preliminary findings predict that the presence of a microvascular clot will accelerate the local deposition of Ap plaques. These data suggest that microvascular lesions could play an important role in Alzheimer's disease pathogenesis. Relevance ~ Alzheimer's disease is the most common cause of dementia in the elderly. Clinically, Alzheimer's disease is often entangled with vascular disease, suggesting that the two diseases are intimately interrelated. In many patients, sucessful treatment will have to address both aspects. This work investigates how the two conditions might worsen each other and will help identify strategies for preventing dementia.